Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH2:21]>CN(C)C=O>[CH2:13]([O:9][CH:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[C:3]1([O:21][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)c(Cl)c1O
Reactant: O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1(OCc2ccccc2)C(Cl)=C(Cl)C=CC1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
In 250 ml of dimethylformamide is dissolved 8.95 g of the compound (II), and 4.80 g (2 equivalent) of 50% sodium hydride oily suspension and 10.25 g (1.3 equivalent) of benzyl bromide are added thereto. The mixture is stirred for 10 minutes under ice cooling, then poured into 200 ml of water, and sparingly soluble crystals are collected by filtration and recrystallized from hexane to give 2.096 g of 1,2-dibenzyloxy-2-hydroxy-3,4-dichlorobenzene, mp. 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:19](OC)(OC)(OC)C>CO>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(C)(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
25.50 g (0,127 mol) of 2-chloro-3-nitrobenzoic acid are dissolved in 50 ml of MeOH, and 3 ml of concentrated sulfuric acid are added. The reaction mixture is heated at boiling for 4 h. Following the addition of 10 ml of trimethyl orthoacetate the mixture is heated at boiling for a further 2 h. After cooling to 0° C. and filtering off the solid by suction, 26.4 g (96 %) of colorless methyl 2-chloro-3-nitrobenzoate are obtained, m.p. 68-70° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][O:15][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](OC(CO)CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](OC(CO)COS(=O)(=O)c2ccc(C)cc2)CC1
Reaction time: 16 h

Procedure:
To a solution of cis/trans-4-(2-hydroxy-1-hydroxymethyl-ethoxy)-cyclohexanecarboxylic acid ethyl ester (3:7) (0.74 g, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) in dichloromethane (30 ml) a catalytic amount of 4-N,N-dimethylaminopyridine was added. A solution of p-toluenesulfonyl chloride (0.57 g, 3.0 mmol) in dichloromethane (10 ml) was added dropwise at room temperature. Stirring for 16 h was followed by partitioning between ethyl acetate (100 ml) and 0.5 M aqueous hydrogen chloride solution (50 ml). The layers were separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.46 g, 38%) as colorless oil. MS m/e: 401 (M+H+)
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:9]([NH:16][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Yield: 40.3 %

Procedure:
Acid, 3-oxocyclobutanecarboxylic acid (10 g, 0.087 mol), benzylamine (10.5 mL, 0.96 mol), and triethylamine (38 mL, 0.26 mol) were dissolved in DMF (100 mL). BOP (38.7 g, 0.087 mol) was added at 0° C. under stirring in argon. The mixture was stirred at 20° C. for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was purified by chromatography (silica gel, 63-100 μm, 1 L, CCl4→CHCl3, CHCl3/MeOH 100:0→95:5). The title compound (7.12 g, 40%) was obtained as a colorless oil. 1H NMR-data (DMSO-d6): 8.62 (br.s, 1H, NH); 7.21-7.36 (m, 5H, Ph); 4.32 (d, 2H, CH2, J=6.1 Hz); 3.10-3.28 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:21])=[CH:7][CH:6]=1)[CH3:3].[CH3:24][N:25]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH3:26].[O-:36][CH2:37][CH3:38].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8]([CH:9]2[CH:32]([C:31]3[CH:34]=[CH:35][C:28]([CH2:27][N:25]([CH3:24])[CH3:26])=[CH:29][CH:30]=3)[C:37](=[O:36])[C:38]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:21])=[CH:17][C:18]([F:20])=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Reactant: CN(C)Cc1ccc(C=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(CN(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (1 g, 31.9 mmol) and 4-((dimethylamino) methyl)benzaldehyde (0.52 g, 31.9 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (220 mg, 95.8 mmol) in ethanol (20 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, dichloromethane/methanol=10:1 to 20:3) to give the title (520 mg, yield 33%). LC-MS (ESI) m/z: 503.
Reaction SMILES: FC1C=C(C2CCN([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)CC2)C=CC=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH2:49][CH2:50][CH3:51])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37]([OH:39])=O.CN(C(ON1N=N[C:62]2[CH:63]=[CH:64][CH:65]=[N:66][C:61]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:66]2[CH2:65][CH2:64][C:63]([C:40]3[CH:36]=[CH:35][CH:43]=[C:42]([F:44])[CH:41]=3)([CH2:14][CH2:15][N:16]3[C@H:17]4[CH2:23][CH2:22][C@@H:21]3[CH2:20][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:18]4)[CH2:62][CH2:61]2)=[O:39])=[CH:40][C:41]([S:45]([NH:48][CH2:49][CH2:50][CH3:51])(=[O:47])=[O:46])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCN1CCC(c2cccc(F)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Product: CCCNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c(Cl)cc1F
Yield: 40 %

Procedure:
0.366 g (0.82 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.363 g (1.23 mmol) 2-chloro-4-fluoro-5-[(propylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 90:5:5 acetonitrile: ammonium hydroxide: water in acetonitrile. 0.24 g obtained (40% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.04-8.15 (br, 1H), 7.69-7.90 (m, 2H), 7.32-7.52 (m, 3H), 7.19-7.26 (m, 2H), 7.01-7.15 (m, 3H), 4.41-4.56 (m, 1H), 3.86-3.98 (m, 1H), 3.19-3.43 (m, 6H), 2.97-3.08 (m, 1H), 2.77-2.88 (m, 2H), 2.44 (s, 3H), 2.28-2.41 (m, 2H), 1.96-2.17 (m, 2H), 1.71-1.92 (m, 9H), 1.56-1.64 (m, 2H), 1.31-1.42 (m, 2H), 0.73-0.81 (m, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH3:11])[C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)[CH:2]=[CH2:3].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=3)[CH:20]=[N:19]2)=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=1>>[CH2:1]([N:4]([CH3:11])[C:5]1[S:6][C:7](=[CH:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH2:17][C:16]2[CH:29]=[CH:30][C:13]([Cl:12])=[CH:14][C:15]=2[C:31]([F:34])([F:32])[F:33])[N:19]=[CH:20]3)[C:8](=[O:10])[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C)C1=NC(=O)CS1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: C=CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
2-(Allyl-methyl-amino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 2-(allyl-methyl-amino)-thiazol-4-one and 1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure E.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3C=CC=[C:25](Cl)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][SH:3])[CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(CCCN2CCN(c3cccc(Cl)c3)CC2)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: SCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Yield: 134.8 %

Procedure:
The procedure described in Example 1(b) was followed, using 7.6 g of thiourea, 22.9 g of 1-[3-(4-chlorophenyl)propyl]-4-(3-chlorophenyl)piperazine dihydro- chloride, 5.8 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 14.1 g (65% of theory) of 3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 238°-242° C.
Reaction SMILES: Cl.N1C=CC=C[CH:3]=1.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][C:15]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:14][CH:13]=2>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[CH:10][C:9]3[N:8]=[CH:3][N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[C:17]=2[CH:16]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccc(OCc4ccccc4)cc3c21

Procedure:
For Examples 70-72, the following procedure was used. Under a nitrogen atmosphere, the reagent from the table below (1.5 equivalents) and pyridine hydrochloride (0.01-0.02 equivalents) were added to a solution of tert-butyl {4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (29-36 mmol, 1 equivalent) in toluene (200 mL), and the reaction was heated at reflux for three to five hours. The toluene was removed under reduced pressure. The residue was dissolved in a small amount of toluene, which was removed under reduced pressure. This was repeated three times. The resulting solid was dried under high vacuum at 100° C. to provide the tert-butyl {4-(8-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate with the substituent indicated in the table below.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH2:12]([C@@H:3]([C:4](=[O:5])[NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:2][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)CNC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-methyl 2-(2-amino-4-methylpentanamido)acetate hydrochloride (4w) in THF was added 6-((tert-butoxycarbonyl)amino) hexanoic acid, HATU and DIPEA. The reaction was stirred at room temperature for 18 h. The mixture was then filtered through Celite. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=50/1) to give (S)-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@H:8]([C:13]([OH:15])=[O:14])CC(C)C.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][CH2:8][C:13](=[O:14])[OH:15]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Ala 0.98 (1); Leu 0.76 (1); Phe 0.81 (1) LSIMS (Liquid Secondary Ion Mass Spectrometry) (M+H+)=647, (theoretical value)=647
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:7]=1[C:8]#[N:9])[CH:2]([CH3:4])[CH3:3]>CC(O)=O.C1COCC1.CCOC(C)=O.[Fe]>[NH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]=1[C:8]#[N:9]
Reactant: CC(C)COc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)COc1cccc(N)c1C#N
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 2-isobutoxy-6-nitrobenzonitrile (Example 41c, 34.3 g, 0.156 mol) in AcOH/THF (1:1 by volume, 250 mL) was added iron powder (17.36 g, 0.311 mol) in one portion. The stirred suspension was heated to reflux for 30 minutes. After it was cooled down to room temperature, the reaction solution was diluted with EtOAc (1 L). The solid was removed by filtration, and the filtrate was washed subsequently with water (300 mL×2), 1N NaOH (300 mL), saturated Na2CO3 aqueous solution (300 mL), brine (300 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a yellow oil (16.4 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.8 Hz, 6H), 1.96-2.02 (m, 1H), 3.75 (d, J=6.4 Hz, 2H), 5.96 (s, 2H), 6.17 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 1H). MS 191 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:20]Br.O>CC(O)=O>[Br:20][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nc(Br)cnc1N1CCNCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a mixture of 2-chloro-3-(1-piperazinyl)pyrazine (5.94 g, 30 mmol, from Example 90, Step 1) and Na2CO3 (6.0 g, 57 mmol) in AcOH (25 mL) was added a solution of Br2 (6.00 g 38.0 mmol) in AcOH (25 mL) dropwise at room temperature. The reaction mixture was stirred overnight. Water (50 mL) was added and the solution was stirred for 30 min and then concentrated to a small volume. Water (20 mL) was added and the solution was basified to pH 9 by adding solid Na2CO3. The mixture was extracted with CH2Cl2 containing 10% MeOH. The combined extract was evaporated to dryness and the residue was recrystallized from MeOH to give 7.43 g (89%) of the title compound: mp 114-115° C. HRMS m/z calcd for C8H10BrCIN4 (M)+275.9777, found 275.9765.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)=[O:10])[CH2:5]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:46][C:47]1([F:53])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:46][C:47]1([F:53])[CH2:52][CH2:51][N:50]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:9]([N:6]2[CH2:7][CH2:8][CH:4]([N:3]([CH3:23])[CH3:2])[CH2:5]2)=[O:10])=[CH:19][CH:18]=3)=[O:21])[CH2:49][CH2:48]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)C1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1

Procedure:
The title compound was synthesized in analogy to example 1, from (RS)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, as a colorless solid (77%).
Reaction SMILES: [CH2:1]([N:8]([CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=1)[CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.CC(O)=O.[Fe].O.O.O.O.[Fe](Cl)Cl>[NH2:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH2:38][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@@H:10]([C:19]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:25]3[C:20]=2[CH:21]=[CH:22][C:23](=[O:37])[NH:24]3)[O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])=[CH:45][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl[Fe]Cl
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(N)cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
A mixture of 5-[(R)-2-{benzyl-[2-(4-nitrophenyl)ethyl]amino}-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (3.00 g, 4.52 mmol); iron (2.52 g, 45.2 mmol) and iron(II) chloride tetrahydrate (0.18 g, 0.90 mmol) in EtOH (27.3 mL) and AcOH (9.09 mL) was stirred at 80° C. overnight. The reaction mixture was filtered through a pad of Celite, washing with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without any further purification.
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)cc(Br)c2)cc1
Yield: 36 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (1) in Example 3, the reaction of 3,5-dibromobenzoyl chloride (20.13 g, 0.06747 mole) with 4-octoxybenzoyl hydrazide (17 g, 0.06747 mole) gave the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (12.87 g, 36% yield). Cyclocondensation of the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]-benzohydrazide (12.17 g) with POCl3 (63 mL) gave the required 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (5) (6.12 g, 52% yield).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)[CH3:3].[CH3:14][S-:15].[Na+]>C(O)C>[CH3:14][S:15][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: C[S-]
Reactant: CC(Br)c1ccc(C(F)(F)F)nc1
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1-bromoethyl)-2-trifluoromethylpyridine (1.02 g, 4.0 mmol) in ethanol (30 mL) was cooled to 0° C. under an atmosphere of nitrogen. Sodium methyl mercaptide (364 mg, 5.2 mmol) was added batchwise. Once added, the ice bath was removed and the reaction stirred at room temperature under nitrogen overnight. TLC (9:1, hexane:EtOAc) showed complete reaction. The turbid solution was quenched with water and extracted with ether. The organic layer was then washed with brine and dried (MgSO4). The solvent was removed in vacuo to provide the crude product as a pale yellow liquid, 0.83 g (93%); 1H NMR (CDCl3) δ 8.65 (s, 1H), 7.89 (d, 1H), 7.67 (d, 1H), 3.93 (q, 1H), 1.94 (s, 3H), 1.62 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:25][CH2:26][CH2:27][O:28][C:29]1[C:36]([CH3:37])=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[CH3:38]>C(O)C.[Cu](Cl)Cl>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=3)[N:1]=[C:33]2[C:32]2[CH:35]=[C:36]([CH3:37])[C:29]([O:28][CH2:27][CH2:26][OH:25])=[C:30]([CH3:38])[CH:31]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(S(C)(=O)=O)cc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide (0.21 g, 0.58 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.13 g, 0.64 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.440 g, 3.27 mmol) and the reaction mixture was refluxed for 48 hours. The solvent was evaporated in vacuo and the product was extracted with dichloromethane. The solvent was evaporated in vacuo and the residue was triturated with ether and methanol/ethyl acetate and filtered off, to obtain the title compound as a white solid. Yield: 0.13 g (43%). MP 258.8-260.2° C. 1H-NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 8.28 (d, 1H), 7.94 (d, 1H), 7.19 (m, 2H), 7.03 (m, 2H), 7.01 (s, 2H), 3.91 (m, 2H), 3.79 (d, 2H), 3.17 (s, 3H), 2.58 (m, 1H), 2.18 (s, 3H), 2.03 (m, 1H), 1.60 (m, 2H), 1.21 (d, 3H), 0.78 (t, 3H). MS (ES+) m/z: 521.66 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[N:8]1([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[CH:15]=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1cncc(N2CCOCC2)c1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1cncc(N2CCOCC2)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stirred for 1 h. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4-ylnicotinaldehyde (70 mg, 90%) as a crude product. 1H NMR (400 MHz, CDCl3): 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).